Our research is aimed at understanding the basic question in developmental biology: "During development, how does a cell's fate become specified?" Or, more simply, how does a cell know to become a muscle cell and not a nerve cell or some other type of cell? Specific proteins contribute to a cell's fate, and regulators called transcription factors control the presence of these proteins. A careful examination of how transcription factors perform their function, therefore, will be critical for understanding cell-fate specification. We are studying cell-fate specification in the context of transcriptional regulation in the mesoderm. The mesoderm is the middle embryonic germ layer from which muscle, connective, and heart tissues are derived. The model organism that we use is the nonparasitic soil nematode, Caenorhabditis elegans. C. elegans have a number of advantages for studying development such as transparent cells, complete genome information, and powerful genetics. The animals also have a short generation time of 3 days allowing rapid experimentation. In addition, the nematodes have several tissue types that are mesodermal in origin and yet a small total number of mesodermal cells so that we can focus on events at a single cell level.

A number of transcription factors play a role in cell-fate specification. We are focusing on a basic helix-loop-helix (bHLH) transcription factor CeTwist, which plays a role in patterning and specification of the mesoderm in C. elegans. Our aim is to understand the mechanism by which this factor controls the expression of target genes in a diverse set of mesodermal cells. CeTwist forms heterodimers with another bHLH factor, CeE/DA. As first step towards our aim, we have identified target genes of the heterodimers using microarrays representing all of the transcripts in the C. elegans genome (Wang et al., 2006). We have also explored the mechanism of regulation of one of the target genes, arg-1 (Zhao et al., 2007). In the promoter region of arg-1, we have found three elements that are uniquely required for the expression pattern of arg-1. Currently, we are pursuing various lines of investigation to understand how these elements are uniquely used by the bHLH factors for regulating transcription in individual cells. Furthermore, we have identified a role for CeTwist containing homodimers (manuscript in preparation) and are using a microarray approach to identify target genes of the homodimers.Finally, in order to understand the temporal and spatial regulation of the CeTwist and CeE/DA genes, we are using a reporter gene approach to identify elements important for their expression. Collectively, we expect our multifaceted approaches will provide a mechanistic understanding of target gene control by bHLH factors in mesoderm development.

Our work has important human health consequences. Mutations in the human Twist gene are associated with a developmental disorder called Saethre-Chotzen syndrome in which patients have craniofacial and digit defects. Mutations in human homologs of several CeTwist target genes, including arg-1, are associated with other human syndromes causing defects similar to those seen in Saethre-Chotzen patients, and similar diseases exist whose underlying genetic basis is not yet known. Thus, C. elegans genes identified by the genetic and molecular approaches in our laboratory will reveal candidates for defective human genes in individuals suffering from related developmental syndromes. We have already found several candidate genes and expect that a careful understanding of their regulation will help us to understand more about craniofacial diseases in humans.

Research Funding:

Dr. Corsi's work is funded by an R15 Academic Research Enhancement Award (AREA) grant from the National Institute of Dental and Craniofacial Research at the National Institutes of Health.